Selective nuclear receptor modulators

Table 15.3-2 Examples of therapeutic profiles for designer, tissue-selective nuclear receptor modulator ligands...

A transcription factor implicated in acute promyelocytic leukemia A form of the retinoic acid receptor A member of the nuclear receptor family A member of the nuclear receptor family A form of the retinoic acid receptor Selective estrogen receptor modulators A channel locus associated with the Long QT syndrome... 

Miner, J.N., Burnett, K, Chang, W. et al. (21 September 2005) Steroid receptor modulators approaches to selectivity for androgen receptor, Tissue-Selective Nuclear Receptor Symposia, Keystone Meeting. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Eplerenone, a selective MR modulator, was discovered decades ago and has recently received approval as a treatment for hypertension [77]. This synthetic steroid derivative has a higher specificity for MR relative to other nuclear receptors and works as a partial antagonist of aldosterone [78]. 

A field which is still far from being completely understood on a molecular level is the nuclear receptor-cofactor interaction. Luc Brunsveld, B. Vaz and S. Moddinghoff give an introduction to our current knowledge in this field and explain why these interactions might be attractive targets for more selective modulators. 

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